The alpha and gamma-pyrones are classes of compounds shown to be linked to several behavioral and pharmacological characteristics including sedative, anxiolytic, neuroprotective and antioxidative effects. Specifically, a gamma-pyrone derivative called maltol has been isolated from passion flower and shown to cause central nervous system (CNS) sedation and a reduction in caffeine-induced agitation and spontaneous motility in animals; these effects are mediated via activation of gamma-aminobutyric acid (GABA) receptors (Soulimani et al., J. Ethnopharmacology 57:11, 1997; Dhawan et al., J. Ethnopharmacology 78: 165-70, 2001). Other members of this family, the gamma-pyrones comenic, meconic and chelidonic acids have been shown to exert sedative effects via interaction with opiod receptors (U.S. Patent Application No. 2003/0181516).
The GABAa receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, GABA, acts. Widely, although unequally, distributed through the mammalian brain, these receptors, and in particular a complex of proteins called the GABAa receptor, cause alterations in chloride conductance and membrane polarization (Mehta and Ticku, Brain Res. Brain Rev. 29:196-217, 1999).
Benzodiazepine drugs exert their hypnotic, analgesic and anxiolytic actions by interacting with the benzodiazepine binding sites at the GABAa receptor. In addition to the benzodiazepine-binding site, the GABAa receptor contains several distinct sites of interaction with other classes of drugs that modulate GABAergic activities, including nonbenzodiazepine hypnotics (e.g. zolpidem, zaleplon, indiplon, zopiclone) (Sanger, CNS Drugs 18 (Suppl. 1):9-15, 2004), steroids, pictrotoxin and barbiturates. The benzodiazepine and non-benzodiazepine binding sites in the GABAa receptor complex do not overlap with the GABA or any of the other drug binding sites (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., pp. 145-148, Oxford University Press, New York, 1991). Electrophysiological studies indicate that the major action of the benzodiazepines and nonbenzodiazepines is enhancement of GABAergic inhibition of neuronal excitability. This is due to potentiation of the GABA-induced chloride influx into the cells and subsequently membrane hyperpolarization. The clinically important alloseteric modulation of the GABA receptors by benzodiazepines and non-benzodiazepines has been an area of intense pharmacological discovery in recent years. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects (Dawson et al., CNS Spectr. 10:21-7, 2005).
The major disorders for which GABAa receptors represent important therapeutic targets include anxiety disorders, cognitive disorders, epilepsies, mood disorders, schizophrenia, pain and sleep disorders. GABA receptor modulators are known to play an important role in sleep and positive allosteric modulators of GABAa receptors are widely used to promote and maintain sleep in a variety of primary and secondary sleep disorders (Sanger, CNS Drugs, 18 (Suppl. 1):9-15, 2004).
While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, increased risk of falls and a tendency for tolerance and drug dependence. An important aspect of these activities is the residual daytime effect resulting in impairment of daytime vigilance. Therefore new GABA receptor modulators with less untoward side effects are sought.
Indole compounds, specifically those related to serotonin (5-hydroxytryptamine; 5-HT) and melatonin (N-acetyl-5-methoxy-tryptamine) have profound CNS effects and thus impinge on sleep, wakefulness, appetite and mood. There are an extensive number of clinically relevant areas where the involvement of the melatonin system has been demonstrated (Bubenik et al., Biol. Signals Recept. 7:195-219, 1998). These include regulation of core body temperature (Strassman et al., J. Appl. Physiol. 71:2178-2182, 1991; Krauchi et al., J. Appl. Physiol. 83:134-9, 1997), immune responses, (Maestroni and Conti, J. Neuroimmun. 28:167-176 1990; Fraschini et al., Acta Oncol. 29:775-776, 1990; Guerrero and Reiter, Endocr. Res. 18:91-113, 1992), pubertal development, ovulation, seasonal reproduction, retroperitoneal and epididymal fat, as well as plasma insulin, leptin, growth hormone and ghrelin levels (Rasmussen et al., Endocrinology 140: 1009-12, 1999; Cramer et al., Arzeneim-Forsch 26:1076-1078, 1976; Wright et al., Clin. Endocrinol. 24:375-382, 1986, Paccotti et al., Chronobiologia 15:279-288, 1988; Valcavi et al., Clin. Endocrinol. 39:139-199, 1993; Mustonen et al., Endocrine 16:43-6, 2001), cortisol rhythms, ocular pressure (Sampes et al. Curr. Eye Res. 7:649-653, 1988; Rhode et al., Ophthalmic Res. 25:10-15, 1993), blood pressure (Scheer et al., Hypertension 43-192-7, 2004), glucose metabolism, ghrelin, leptin and body fat mass, vasopressin and urine excretion (Song et al., FASEB J. 11:93-100, 1997; Yasin et al., Brain Res. Bull. 39:1-5, 1997). In some instances, psychiatric disorders may have underlying chronobiological etiologies (e.g. seasonal effective disorder) and are definite candidates for melatonin therapy (Miller, Altem. Med. Rev. 10:5-13, 2005). Melatonin also acts as a free radical scavenger and anti-oxidant (Pooggeler et al., J. Pineal Res. 14:151-168, 1993).
There is very strong evidence that melatonin specifically regulates sleep and wakefulness in humans. Melatonin has been administered to re-synchronize circadian rhythms that are out of phase with the local photoperiodical cycle. For example, sleep/wake disorders caused by rapid crossing of time zones (et lag), delayed sleep phase syndrome (DSPS) patients, shift work and total blindness, can be treated with melatonin or melatonin analogs (see U.S. Pat. Nos. 4,600,723 and 4,666,086 of Short et al. and U.S. Pat. No. 5,242,941 of Lewy et al.). In addition, melatonin has direct sedative/hypnotic properties in both normal and insomniac human subjects (e.g., Luboshizsky et al., Sleep Med. Rev. 2:191-202, 1998; U.S. Pat. No. 5,403,851 of D'Orlando et al.). Sleep disorders in the elderly have been shown to respond to melatonin treatment (Garfinkel et al., Lancet 346:541-543, 1995; Pandi-Perumal et al., Exp. Gerontol. 40:911-25, 2005; U.S. Pat. No. 5,498,423 of Zisapel). Melatonin and its analogs reduce latency to sleep onset in patients with insomnia (Roth et al., Sleep, 28:303-7, 2005, Zhdanova et al., Clin. Pharmacol. Ther. 57:552-8, 1995) or depression (Papp et al., Neuropsychopharmacology 28:694-703, 2003) and particularly enhance the restorative value of sleep in insomnia patients, resulting in enhanced daytime vigilance (Zisapel, PCT Patent application No. WO 03/015690).
There is a wide spectrum of symptomatic responses to melatonin treatments in different disorders. These include anxiety (Loiseu et al., Eur. Neuropsychopharmcol. 2005), seizures (Munoz-Hoyos et al., J. Child. Neurol. 13:501-9, 1998), pain (Ray et al., Indian J. Med. Sci. 58:122-30, 2004), cluster headache and migraine (Peres, Cephalalgia 25:403-11, 2005), depression, mania and schizophrenia (see Dobocovich “Antidepressant Agents”, U.S. Pat. No. 5,093,352; Shamir et al., J. Clin. Psychopharmacol. 20:691-4, 2000), glaucoma, aging, stress (Armstrong and Redman, Med. Hypotheses 34:300-309, 1991; Reiter, Bioassays 14: 169-175, 1992), hypertension (Scheer et al, Hypertension 43:192-7, 2004, Zisapel, U.S. patent application Ser. No. 10/169,467), drug withdrawal syndromes (Zisapel, U.S. Pat. No. 6,469,044), osteoporosis (Cardinali et al., J. Pineal Res. 34:81-7, 2003), various cancers (Gonzalez et al., Melanoma Res. 1:237-243, 1991; Lissoni et al., Eur. J. Cancer 29A:185-189, 1993; Blask et al., Endocrine 27:179-88, 2005; U.S. Pat. No. 5,196,435 of Clemens et al. and U.S. Pat. No. 5,272,141 of Fraschini et al.), benign tumors and proliferative diseases such as Benign Prostatic Hyperplasia (BPH) (U.S. Pat. No. 5,750,557 and European Patent No. EP 0565296B of Zisapel), psoriasis, contraception and fertility, precocious puberty, premenstrual syndrome and hyperprolactinemia (Pevre et al., J. Clin. Endocrinol. Metab. 47:1383-1388, 1978; Purry et al., Am. J. Psychiatry 144:762-766, 1987; Waldhauser et al., Clin. Endocrinol. Metab. 73:793-796, 1991; Bispink et al., J. Pineal Res. 8:97-106, 1990; Cagnacci et al., J. Clin. Endocrinol. Metab. 73:210-220, 1991; Voordouw et al., J. Clin. Endocrinol. Metab. 74:10-108, 1992; see U.S. Pat. Nos. 4,855,305 and 4,945,103 of Cohen et al. and U.S. Pat. No. 5,272,141 of Fraschini et al.).
Melatonin is beneficial for the treatment and prevention of neurodegenerative disorders (Skene et al., Brain Rev. 528:170-174, 1990; Feng et al., J. Pineal Res. 37:129-36, 2004), ischemic stroke (Cho et al., Brain Research 755:335-338, 1997; Reiter et al., Exp. Biol. Med. 230:104-17, 2005), Alzheimer's disease (Pappola et al., J. Neurosci. 17:1683-90, 1997; Feng and Zhang, Free Radic. Biol. Med. 37:1790-801, 2004) and sudden infant death syndrome (SIDS) (U.S. Pat. No. 5,500,225 of Laudon et al.).
Three melatonin receptor subtypes have been identified so far: MT-1, MT-2 and dihydronicotinamide riboside-quinone reductase 2 that is sometimes referred to as MT-3 or ML2 melatonin receptors (Dubocovich et al., IUPHAR media, London, UK, 187-93, 1998; Maillet et al., FEBS Lett. 3:578-116-20, 2004). MT-1 is localized in the CNS and in peripheral organs such as the kidneys and the urogenital tract, while MT-2 is located mainly in the central nervous system. There are no physiological activities ascribed to the MT-3 (ML2) sites. In addition, melatonin interacts with intracellular proteins such as calmodulin (Anton-Tay et al., J. Pineal Res. 24:35-42, 1998) and tubulin-associated proteins (Cardinali et al., J. Pineal Res. 23:32-9, 1997). Retention patterns of radioactive-melatonin injected into rats demonstrate melatonin accumulation in the brain, pituitary, lung, heart, gonads and accessory sex organs (Withyachumnamkul et al., Life Sci. 12:1575-65, 1986).
It is clear that there exists a broad range of therapeutic uses for melatonin and its analogs. Accordingly, it is of continuing interest to identify novel compounds that interact with the melatoninergic system as potential therapeutic agents (Zlotos, Arch. Pharm. Chem. Life Sci. 338:229-247, 2005). These compounds may offer longer duration, selective localization and greater efficacy to those of melatonin.
Serotonin (5-HT) is now known to modulate numerous physiologic and behavioral systems that explain the many 5-HT based drugs used as treatments in very different clinical conditions. There are extensive therapeutics directed at increasing or decreasing 5-HT function at selected sites, in widely different clinical conditions. Probes of 5-HT turnover in CNS and peripheral tissue have demonstrated alterations in 5-HT metabolism to be associated with a wide number of clinical conditions, and many drugs, such as antidepressants, antipsychotics, and anxiolytics, have been shown to alter 5-HT function in several disorders. The development and widespread clinical use of selective 5-HT reuptake inhibitors (SSRI), and the preclinical delineation of the multiple 5-HT receptor subtypes and their couplings to intracellular messenger systems and the development of drugs selectively acting on these systems, have catalyzed an explosion of new research information in this field. It is now clear that the 5-HT systems are extremely diverse, and that they are involved in a multitude of physiologic and behavioral processes. In contrast, the development of specific 5-HT receptor agonists and antagonists have led to more specific targeted therapeutic interventions such as the use of the 5-HT agonist, sumatriptin, in migraine and cluster headache, and the 5-HT3 antagonist, ondansetron in the control of nausea and emesis.
There are an extensive number of clinically relevant areas in which the involvement of the 5-HT system has been demonstrated. These include mood regulation, fear and anxiety, learning and memory, cognitive control, appetite and eating regulation, sleep, sexual function, impulse control, developmental behavioral regulation, aging and neurodegeneration, motivation and reward, pain sensitivity, emesis, myoclonus, neuroendocrine regulation, circadian rhythm regulation, stress response and carcinoid syndrome.
There is a wide spectrum of symptomatic responses to selective serotonin reuptake inhibitor (SSRI) treatments in different disorders. The increased availability of a number of SSRI's for clinical use has led to treatment trials in a wide variety of different clinical conditions. Placebo controlled studies have demonstrated positive results of SSRI treatment in: depression, obsessive-compulsive disorder (OCD), panic disorder, premenstrual syndrome, bulimia nervosa, autistic disorder, diabetic neuropathy, and diabetic obesity. The wide spectrum of different clinical conditions that have been reported to demonstrate a symptomatic response following SSRI treatment includes major depression, depression secondary to medical condition, post stroke depression, dysthymia, seasonal affective disorder, OCD, panic disorder, social phobia, borderline personality disorder, depersonalization syndrome, body dysmorphic syndrome, premenstrual syndrome, postpartum disorders, bulimia nervosa, post traumatic stress disorder, autistic disorder, attention deficit, hyperactivity disorder, Tourette's syndrome, trichotillomania, onychophagia, Prader-Willi syndrome, paraphillias and sexual addictions, premature ejaculation, migraine prophylaxis, diabetic neuropathy, pain syndromes, obesity, weight gain in smokers, alcoholism, emotional liability following brain injury, sleep paralysis, pathologic jealousy, chronic schizophrenia, self-injurious behavior, arthritis, Raynaud's phenomenon, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, upright tilt syncope, intention myoclonus and neuroendocrine regulation.
The preclinical data on 5-HT indicate that the 5-HT systems are predominantly modulatory and that most 5-HT effects interact with the ongoing status of the other involved neurotransmitter systems. The neuroanatomy of the 5-HT system suggests that up to 60% or more of 5-HT released may not be at synapses. Thus, 5-HT effects would not be expected to be highly anatomically localized or demonstrate the properties associated with systems that more directly mediate neurotransmission. The modulatory nature of the 5-HT systems can be seen at the clinical level through interactions with other neurotransmitter systems. In behaving animals, the activity of brain serotonergic neurons is closely tied to the sleepwake-arousal cycle: highest firing rate during active waking or arousal, intermediate level of discharge during quiescent states and slow wave sleep, and virtual silence during rapid-eye movement sleep. Some SSRI compounds are associated with untoward weight loss or excessive weight gain, insomnia and sexual dysfunction.
The widespread involvement of the 5-HT systems in modulating the physiologic functions of a large number of different and important biological systems, coupled with the rapid progress of the molecular biological approach in discovering new 5-HT receptor subtypes, should foster increased research activity directed at the development of clinically applicable 5-HT modulators that can be endowed with other pharmacological properties in order to optimize the parameters of drug use for the clinical effect.
Novel compounds related to melatonin or serotonin and pyrones, but with pharmacological or pharmacokinetic profiles different from these molecules, are likely to be important new pharmaceuticals. For examples, see U.S. Pat. No. 5,403,851, which discloses the use of substituted tryptamines, phenylalkylamines and related compounds, in order to treat a number of pharmaceutical indications including sleep disorders, endocrine indications, immune-system disorders etc. PCT Patent Application No. WO 87/00432 describes compositions for treating or preventing psoriasis that contain melatonin or related compounds. U.S. Pat. No. 5,122,535 discloses the production of melatonin and analogs thereof for various therapeutic purposes, including the administration of melatonin in combination with an azidothymidine for the treatment of AIDS. Melatonin analogs based on the bioisosteric properties of the naphthalenic ring and the indole ring have been disclosed in J. Med. Chem. 1992, 35: 1484-1485, EP 662471 A2 950712 of Depreux et al., WO 9529173 A1 951102 of Ladlow et al., U.S. Pat. No. 5,151,446 of Horn et al., U.S. Pat. No. 5,194,614 of Adrieux et al. and U.S. Pat. No. 5,276,051 of Lesieur et al. Melatonin and its analogs may potentiate the effects of GABA receptor modulators (Zisapel, U.S. Patent application No. US20055175692, Zisapel, U.S. Pat. No. 6,469,044).
Insulin resistance and non-insulin-dependent diabetes are prevalent in up to 35% of the population depending upon the age and nature of the subset. In the United States alone, 16 million people have type 2 diabetes and 13 million have impaired glucose tolerance. In fact, type 2 diabetes has reached epidemic proportions worldwide. By 2025, an estimated 300 million people will have diabetes, most of whom will inhabit China, India, and the United States. Because of an aging and increasingly sedentary, obese population with changing, unhealthy diets, insulin resistance is also increasing alarmingly (it is already two to three times more prevalent than type 2 diabetes).
Insulin resistance usually occurs early in the development of type 2 diabetes. An altered balance in the autonomic nervous system and in certain endocrine and inflammatory pathways might contribute to the development of insulin resistance. In diabetes, hyperglycemia further aggravates insulin resistance as well as beta cell dysfunction but the mechanisms causing this phenomenon, i.e. glucotoxicity, are not fully understood. Insulin resistance can be demonstrated in healthy first-degree relatives of type 2 diabetes patients who also have a high risk of developing type 2 diabetes.
The fasting hyperglycemia of type 2 diabetes exists in the presence of hyperinsulinemia; this reflects the presence of insulin resistance in the liver with resultant glycogenolysis and gluconeogenesis. In addition to the impaired insulin suppression of hepatic glucose production, a decrease of insulin-mediated glucose uptake by muscle cells contributes (about 50%) to the resultant hyperglycemia.
Glucose tolerance declines with age because of: 1) increased cell receptor resistance to insulin; 2) intracellular post receptor disturbances and 3) diminished pancreatic islet β-cell sensitivity to insulin and glucose. Insulin resistance, with secondary hyperinsulinemia and/or hyperglycemia, contributes to many disorders associated with aging, i.e., hypertension, obesity, atherosclerosis, lipid abnormalities, coagulopathies and chronic metabolic-perturbations including type 2 diabetes. Insulin is one of the most important anabolic hormones in the body and it is critical for the control of carbohydrate, lipid and protein metabolism. Insulin is secreted from beta cells in the endocrine pancreas. It acts by binding to the transmembrane insulin receptor in the target cells, and this activates the tyrosine kinase domain in the intracellular part of the receptor leading to phosphorylation of insulin receptor substrates (IRS). This starts a cascade of signaling reactions in the cell leading to metabolic effects. The main target tissues of insulin's metabolic action are muscle, liver and adipose tissue. Insulin stimulates glucose uptake in insulin sensitive tissues, mainly skeletal muscle, and it inhibits glucose production in the liver and promotes the storage of glycogen in liver and skeletal muscle. It promotes the delivery of non-esterified fatty acids (NEFA) to adipose tissue where they are stored as triglycerides and lipolysis in fat cells is inhibited. In general, overall protein synthesis is increased.
Recent research suggests that there is a high expression of the cytokine tumor necrosis factor-α (TNF-α) in the adipocytes of obese individuals, and that this TNF-α is a principal contributor to insulin resistance and its subsequent type 2 diabetes of obesity. TNF-α is an important regulator of the processes of apoptosis and thus modulates the volume of tumor, adipose and muscular tissues. It is produced not only by immunocompetent cells but also by adipocytes and muscle cells. This cytokine is activated in tumors and obesity, among other conditions. By acting on the phosphorylation of IRS-1 and phosphatidylinositol 3-kinase (PI-3), by modifying resistance through regulation of the synthesis of the insulin responsive glucose transporter GLUT4, and through interference with insulin signaling (perhaps via leptin), TNF-α promotes insulin resistance and anorexia.
Irrespective of the cause, insulin resistance is associated with widespread and adverse effects on health. This is true even when glucose tolerance is only mildly impaired but not yet in the overt diabetic range. Notable among the adverse effects is the predisposition to vascular disease affecting large blood vessels and an association with hypertension and dyslipidemia (elevated triglycerides and decreased HDL). In fact, this combination of 1) glucose intolerance, 2) insulin resistance, 3) hypertension and 4) dyslipidemia is common enough to have acquired the name Syndrome X, the insulin resistance syndrome or Reaven's syndrome. Clinically it defines hundreds of millions of people worldwide.